DENGUE: EPIDEMIOLOGY PART II

1
DENGUEEPIDEMIOLOGYPART II
SCOTT B HALSTEAD, MD
Director, Research PEDIATRIC DENGUE VACCINE
INITIATIVE
2
EPIDEMIOLOGY

• Risk factors for severe disease.
• Sequential dengue infection (includes antigenic
  structure of virus)
• Race
• Age
• Host genetic factors
• Nutritional status
• Sex

3
Race

• Caucasian Asian vs African.
• At least 511,2
• Guzman MG et al. AJTMH 42179-184, 1990.
• Halstead SB et al AJTMH 65180, 2001

4
BLACKS ARE RELATIVELY RESISTANT TO SEVERE DENGUE
ILLNESS

• A human resistance gene seems to explain the
  observation that while all dengue virus types
  circulate in Africa no DHF/DSS cases or outbreaks
  of DF have been reported.

5
RACE - SANTIAGO DE CUBA OUTBREAK, 1997
6
(No Transcript)
7
DENGUE NEUTRALIZING ANTIBODIES BY AGE IN 210
CHILDREN RESIDENT IN PORT AU PRINCE, HAITI,
1996.
N (46) (40) (36) (41)
(27) (13) (10) (4)
8
AGE
9
DHF - EFFECT OF AGE, 1981 Cuba Outbreak
GUZMAN MG et al. Int J Infect Dis 618, 2002
10
CAPILLARY FRAGILITY
Gamble J et al. Biochem Soc Med Res Soc 98211-6,
2000.
11
GENETIC ASSOCIATIONSSusceptibility Resistance

• HLA1 HLA-A0207 HLA-A0203
• HLA-B51 HLA-B52
• HLA A24 HLA A33
• Vit D2 t allele/352
• FcR?II3
• DCSIGN4 CD 209 promoter
• TNFa5 TNF 308
• 1. Loke H et al. JID 1841369-73, 2001
• 2. Stephens HA et al. Tissue Antigens 60309-318,
  2002.
• 3. Loke H et al. AJTMH 67102-6, 2001
• 4. Sakuntabthai A et al. Nat Genetics 37507-13,
  2005
• 5. Fernandez-Mestre MT et al. Tissue Ag
  64468-72, 2004

12
NUTRITIONAL STATUS
13
NUTRITIONAL STATUS OF DHF CASES vs. CONTROLS
14

• Effect of nutritional status on dengue disease
  severity1
• Well nourished children
• highly susceptible to severe disease
• Malnourished protected against severe disease
  (protein-calorie malnutrition grade 2 and 3)
• 1. Thisyakorn U et al. CID 16295-297, 1993

15
SEX
16
SEX RATIOS BY DENGUE SYNDROMEBangkok Childrens
Hospital, 1962-64
17
DHF/DSS during primary dengue infections.
18
DHF/DSS in infants, identical to but more severe
than DHF/DSS in children

• Higher case fatality rates, resuscitation
  requires more fluid per Kg body weight than in
  older children with 2o infection.
• Hung NT et al AJTMH 72370, 2005
• Circulating cytokines and cytokine levels during
  acute phase similar to those in older children
  during 2o infection.
• Hung NT et al JID 189221, 2004

19
DSS in a 6 month-old infants with hepatomegaly.
Vietnam
20
INFANT DHF/DSS
21
(No Transcript)
22
WHY DO MATERNAL ANTIBODIES ENHANCE DENGUE DISEASE?

• CENTRAL ROLE OF MACROPHAGES IN SUPPORTING DENGUE
  INFECTIONS IN HUMANS

23
Dengue viruses are adapted to grow in dendritic
cells, monocytes and macrophages.
Complexed with antibodies dengue viruses enter
FcR-bearing cells with great efficiency.
24
IMMUNE ENHANCEMENT OF DENGUE INFECTION(Antibody-D
ependent Enhancement)

• In the presence of dengue ADE antibody
• increased rate of infection
• increase in the number of infected cells.
• increased production of viruses per cell.

25
ADE IN HUMAN DENGUE DEN virus load and disease
severity
26
DEN 3 VIREMIA
?--? DSS ?- ?DHF ?--? DF
LIBRATY DH et al JID 1851213, 2002
27
DISEASE SEVERITY CORRELATES WITH CELLULAR
INFECTION
28
Schematic distribution of dengue 2 viruses in
blood and tissues of 31 rhesus monkeys.
29
(No Transcript)
30
In endemic areas, DHF/DSS annual outbreaks differ
in severity and size.
31
MYANMAR VARYING CFR
YEAR CASES DEATHS CFR
1986 2,192 111 5.06
1987 7,292 222 3.04
1988 1,181 65 5.5
1989 1,196 52 5.78
1990 6,318 182 2.8
1991 8,055 305 3.7
1992 1,514 40 2.63
32
DENGUE VIRUSES, BANGKOK 1973 - 2001
33
WHY?

• Possible effect of
• ADE
• Heterotypic immunity
• Replacement of serotypes
• Clade extinctions
• These possibilities have been explored in
  mathematical models, most are based upon the
  hospital epidemiological data from Bangkok or all
  of Thailand.

34
EFFECT OF ADE ON EPIDEMIC CYCLES

• Enhancement of infection may generate a complex
  and persistent cyclical or chaotic epidemic
  behavior .and coexistence of mutiple strains
• Ferguson N et al. The effect of
  antibody-dependent enhancement on the
  transmission dynamics and persistence of
  mutiple-strain pathogens.Proc Natl Acad Sci USA
  96790-4, 1999

35
EFFECT OF HETEROTYPIC IMMUNITY ON EPIDEMIC CYCLES

• 8-10 year epidemic cycles are accompanied by
  clade extinctions.
• Mathematical model suggests that heterotypic
  immunity is responsible.
• Adams B et al PNAS 103 14234-9, 2006

36
SEROTYPE REPLACEMENT

• DENV -1 replaced DENV 2, 3, 4. Related to
  stochastic event due to low transmission in
  1999-2000?
• Thu HM et al. Myanmar denge outbreak associated
  with displacement of serotypes 2, 3 and 4 by
  dengue 1. Emerg Infect Dis 10693-7, 2004.

37
CLADE EXTINCTIONS DUE TO STOCHASTIC EVENTS

• In Myanmar, clades B and C of genotype I DENV -1
  circulated with clade A genotype III during the
  1990s. After 1998, clade A disappeared leaving
  only clades B and C.
• Thu HM et al Lineage extinction and replacement
  in dengue type 1 virus populations are due to
  stochastic events rather than to natural
  selection. Virol 336163-72, 2005.
• In Thailand, clades of DENV -3 circulating prior
  to 1992 disappeared and were replaced by two
  lineages with common ancestor. Earlier
  extinctions, 1963, 1973?
• Wittke V et al. Extinction and rapid replacement
  of strains of dengue 3 virus during an
  interepidemic period. Virol 301148-156, 2002.